Modification of bioabsorbable stent to reduce thrombogenecity

ABSTRACT

Bioabsorbable polymer scaffolds with coatings are disclosed that include immobilized antithrombotic agents on the scaffolds or in or on the coatings. The agents act synergistically with antiproliferative agents released from coatings by providing hemocompatibility during and without interfering with antiproliferative agent release. Methods of modifying scaffolds and coatings with the antithrombotic agents are disclosed.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to methods of treatment of coronary arterydisease with bioabsorbable polymeric medical devices, in particular,stents.

2. Description of the State of the Art

This invention relates to radially expandable endoprostheses, that areadapted to be implanted in a bodily lumen. An “endoprosthesis”corresponds to an artificial device that is placed inside the body. A“lumen” refers to a cavity of a tubular organ such as a blood vessel. Astent is an example of such an endoprosthesis. Stents are generallycylindrically shaped devices that function to hold open and sometimesexpand a segment of a blood vessel or other anatomical lumen such asurinary tracts and bile ducts. Stents are often used in the treatment ofatherosclerotic stenosis in blood vessels. “Stenosis” refers to anarrowing or constriction of a bodily passage or orifice. In suchtreatments, stents reinforce body vessels and prevent restenosisfollowing angioplasty in the vascular system. “Restenosis” refers to thereoccurrence of stenosis in a blood vessel or heart valve after it hasbeen treated (as by balloon angioplasty, stenting, or valvuloplasty)with apparent success.

Stents are typically composed of scaffolding that includes a pattern ornetwork of interconnecting structural elements or struts, formed fromwires, tubes, or sheets of material rolled into a cylindrical shape.This scaffolding gets its name because it physically holds open and, ifdesired, expands the wall of the passageway. Typically, stents arecapable of being compressed or crimped onto a catheter so that they canbe delivered to and deployed at a treatment site.

Delivery includes inserting the stent through small lumens using acatheter and transporting it to the treatment site. Deployment includesexpanding the stent to a larger diameter once it is at the desiredlocation. Mechanical intervention with stents has reduced the rate ofrestenosis as compared to balloon angioplasty. Yet, restenosis remains asignificant problem. When restenosis does occur in the stented segment,its treatment can be challenging, as clinical options are more limitedthan for those lesions that were treated solely with a balloon.

Stents are used not only for mechanical intervention but also asvehicles for providing biological therapy. Biological therapy usesmedicated stents to locally administer a therapeutic substance. Thetherapeutic substance can also mitigate an adverse biological responseto the presence of the stent. Effective concentrations at the treatedsite require systemic drug administration which often produces adverseor even toxic side effects. Local delivery is a preferred treatmentmethod because it administers smaller total medication levels thansystemic methods, but concentrates the drug at a specific site. Localdelivery thus produces fewer side effects and achieves better results.

A medicated stent may be fabricated by coating the surface of either ametallic or polymeric scaffolding with a polymeric carrier that includesan active or bioactive agent or drug. Polymeric scaffolding may alsoserve as a carrier of an active agent or drug.

The stent must be able to satisfy a number of mechanical requirements.The stent must be capable of withstanding the structural loads, namelyradial compressive forces, imposed on the stent as it supports the wallsof a vessel. Therefore, a stent must possess adequate radial strength.Radial strength, which is the ability of a stent to resist radialcompressive forces, is due to strength around a circumferentialdirection of the stent.

Once expanded, the stent must adequately provide lumen support during atime required for treatment in spite of the various forces that may cometo bear on it, including the cyclic loading induced by the beatingheart. For example, a radially directed force may tend to cause a stentto recoil inward. In addition, the stent must possess sufficientflexibility to allow for crimping, expansion, and cyclic loading.

The treatment of coronary artery disease with a stent may require thepresence of the stent only for a limited period of time. During or partof this limited time a healing process takes place which includeschanges in the structure of the vessel wall, referred to as remodeling.After the healing process is completed, the presence of the stent is nolonger necessary.

Coronary stents made from biostable or non-erodible materials, such asmetals, have become the standard of care for percutaneous coronaryintervention (PCI) since such stents have been shown to be capable ofpreventing early and later recoil and restenosis. However, a stent madeout of such biostable material retains is mechanical or structuralintegrity and remains at the implant site indefinitely unless it isremoved by intervention or is dislodged. Intervention presents risks tothe patient and dislodgement can have significant adverse consequenceson the patient. Leaving the stent at the implant site permanently alsohas disadvantages. One drawback of such durably implanted stents is thatthe permanent interaction between the stent and surrounding tissue canpose a risk of endothelial dysfunction and late thrombosis.

In order to effect healing of a diseased blood vessel, the presence ofthe stent is necessary only for a limited period of time. Thedevelopment of a bioresorbable stent or scaffold obviates the permanentmetal implant in vessel, allows for late expansive luminal and vesselremodeling, and leaves only healed native vessel tissue after the fullabsorption of the scaffold. Stents fabricated from biodegradable,bioabsorbable, and/or bioerodable materials such as bioabsorbablepolymers can be designed to completely erode only after or some timeafter the clinical need for them has ended. Consequently, a fullybioabsorbable stent can reduce or eliminate the risk of potentiallong-term complications and of late thrombosis. However, it is believedthat the bioabsorbable stent can still pose a risk of thrombosis duringthe limited period of time a bioabsorbable stent is present in a vessel.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference, and as if eachsaid individual publication or patent application was fully set forth,including any figures, herein.

SUMMARY OF THE INVENTION

Various embodiments of the present invention include a bioabsorbablestent comprising: a PLLA scaffolding composed of a plurality of strutshaving a thickness between 100 and 200 microns and; a first coatinglayer above all or a portion of the PLLA scaffolding having a thicknessless than 5 microns, wherein the coating layer comprises anantiproliferative drug distributed throughout a coating polymer, whereinimmobilized antithrombotic agent is at an outer surface of the coatinglayer, wherein the coating layer is free of the immobilizedantithrombotic agent below the outer surface of the coating layer,wherein the antithrombotic agent is selected from the group consistingof heparin, non-adhesive proteins, cell adhesive proteins, cell adhesivepeptide sequences, and hydrophilic monomers or polymers.

Further embodiments of the present invention include a bioabsorbablestent comprising: a PLLA scaffolding composed of a plurality of strutshaving a thickness between 100 and 200 microns and; a first coatinglayer above all or a portion of the PLLA scaffolding having a thicknessof less than 5 microns, wherein the first coating layer comprises acoating polymer with an antiproliferative drug distributed through thecoating layer, wherein immobilized antithrombotic agent is distributedthroughout the coating layer, wherein the antithrombotic agent isselected from the group consisting of heparin, non-adhesive proteins,cell adhesive proteins, cell adhesive peptide sequences, and hydrophilicmonomers or polymers.

Additional embodiments of the present invention include a bioabsorbablestent comprising: a PLLA scaffolding composed of a plurality of strutshaving a thickness between 100 and 200 microns and; a first coatinglayer over the PLLA scaffolding having a thickness of less than 5microns, wherein the first layer is composed of an antiproliferativedrug distributed throughout a first coating polymer; a second coatinglayer above the first coating layer having a thickness of less than 2microns, wherein the second coating layer comprises a second coatingpolymer selected from the group consisting of PDLLA and PGLA, whereinimmobilized antithrombotic agent is distributed throughout the secondcoating layer, and wherein the antithrombotic agent is selected from thegroup consisting of heparin, non-adhesive proteins, cell adhesiveproteins, cell adhesive peptide sequences, and hydrophilic monomers orpolymers.

Other embodiments of the present invention include a bioabsorbable stentcomprising: a PLLA scaffolding composed of a plurality of struts havinga thickness between 100 and 200 microns; and at least two coating layersabove all or a portion of the PLLA scaffolding, wherein each coatinglayer has a thickness less than 2 microns, wherein each coating layercomprises a surface eroding polymer, wherein the polymer is selectedfrom the group consisting of hydrophobic aliphatic polyanhydrides,hydrophobic aromatic polyanhydrides, polyester amides, poly(orthoesters), and polyketals, and wherein immobilized antithrombotic agent isat an outer surface of each coating layer.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts an exemplary stent scaffolding.

FIGS. 2A-C represent a schematic representation of an exemplaryembodiment depicting the properties of an implanted bioabsorbable stentas a function of time.

FIG. 3 depicts a cross-section of a surface region of a stent showing acoating layer over a scaffolding with antithrombotic agent immobilizedat the surface of the coating layer.

FIG. 4 depicts a cross-section of a surface region of a stent showing acoating layer over a scaffolding with immobilized antithrombotic agentthroughout the coating layer.

FIG. 5 depicts a cross-section of a surface region of a stent showingtwo coating layers over a scaffolding with immobilized antithromboticagent throughout the outer coating layer.

FIG. 6 depicts a cross-section of a surface region of a stent showingtwo coating layers over a scaffolding with immobilized antithromboticagent at the surface of each coating layer.

DETAILED DESCRIPTION OF THE INVENTION

Various embodiments of the present invention relate to a bioabsorbablestent and methods of making thereof for treatment of coronary arterydisease. These embodiments include a stent scaffolding with a coatinghaving immobilized antithrombotic agents that reduce or preventthrombosis prior to endothelialization of the stent. The embodimentsfurther include a stent scaffolding or its coating having immobilizedendothelialization-promoting agents.

Coronary artery disease refers to a condition in which the arteries thatsupply blood to heart muscle become hardened and narrowed or stenotic.This is due to the buildup of cholesterol and other material, calledplaque, on their inner walls. Such narrowed or stenotic portions areoften referred to as lesions. Coronary artery disease includesrestenosis which refers to the reoccurrence of stenosis.

A stent may include a pattern or network of interconnecting structuralelements or struts. FIG. 1 depicts a view of a stent 100. In someembodiments, a stent may include a body, backbone, or scaffolding havinga pattern or network of interconnecting structural elements 105. Stent100 may be formed from a tube (not shown). FIG. 1 illustrates featuresthat are typical to many stent patterns including cylindrical rings 107connected by linking elements 110. The cylindrical rings are loadbearing in that they provide radially directed force to support thewalls of a vessel. The linking elements generally function to hold thecylindrical rings together and do not contribute significantly to thesupport of the lumen. The structural pattern in FIG. 1 is merelyexemplary to illustrate the basic structure of a stent pattern.

A stent such as stent 100 may be fabricated from a polymeric tube or asheet by rolling and bonding the sheet to form the tube. A tube or sheetcan be formed by extrusion or injection molding. A stent pattern, suchas the one pictured in FIG. 1, can be formed in a tube or sheet with atechnique such as laser cutting or chemical etching. The stent can thenbe crimped on to a balloon or catheter for delivery into a bodily lumen.

In general, a stent can be made partially or completely from abiodegradable, bioabsorbable, or biostable polymer. A polymer for use infabricating a stent can be biostable, bioabsorbable, biodegradable orbioerodable. Biostable refers to polymers that are not biodegradable.The terms biodegradable, bioabsorbable, bioresorbable, and bioerodableare used interchangeably and refer to polymers that are capable of beingcompletely degraded and/or eroded when exposed to bodily fluids such asblood and can be gradually resorbed, absorbed, and/or eliminated by thebody. The processes of breaking down and absorption of the polymer canbe caused by, for example, hydrolysis and metabolic processes.

In general, in order to facilitate healing of a diseased section of avessel, the presence of a stent is necessary for only a limited periodof time. Therefore, a stent made from a biodegradable polymer isintended to remain in the body for a duration of time until its intendedfunction of facilitating healing a diseased section of a blood vessel iscompleted. After the process of degradation, erosion, absorption, and/orresorption has been completed, no portion of the biodegradable stent, ora biodegradable portion of the stent will remain at the treated sectionof the blood vessel. In some embodiments, very negligible traces orresidue may be left behind.

Additionally, the stent can further include a therapeutic coating orlayer above all or a portion of the scaffolding. The coating can becomposed of a bioabsorable polymer with one or more therapeutic agentsdispersed or dissolved in the polymer. The therapeutic agents caninclude, but are not limited to, antiproliferatives, andanti-inflammatories.

After deployment, the stent maintains patency of the diseased sectionfor a limited period of time until chemical degradation results indegradation of the radial strength to the point that the stent can nolonger support the walls of the section of the vessel. The bioabsorbablestent provides patency to the stented segment for a finite period oftime, the radial strength of the stent deteriorates, making the stentunable to continue to provide patency to the vessel walls. The loss ofradial strength is followed by a gradual decline of mechanicalintegrity, gradual loss of mass from the stent, and eventuallydisappearance of the stent from the stented segment. The time dependentradial strength profile of the stent includes an initial period afterintervention in which the stent maintains its radial strength to preventnegative remodeling of the vessel which is then followed by a loss ofradial strength.

The stent may include a coating to release anitproliferative agent tocontrol restenosis during an initial period caused by smooth muscle cellproliferation (SMP). The drug release declines to zero to allow healingprocesses to occur. The stent may be designed to provide a releaseprofile which controls proliferation during smooth muscle cellproliferation, but terminates soon enough to allow complete or almostcomplete endothelialization prior to substantial mass loss andmechanical integrity loss. The drug release profile may decline to zerobetween 3-4 months after intervention. This allows forendothelialization of stent struts between 4 and 6 months afterintervention.

FIGS. 2A-C depict a schematic representation of exemplary time dependentbehavior of a bioabsorbable stent after intervention at an afflictedsection of a vessel. In addition, FIGS. 2A-C also show expectedbiological responses of the vessel to the stent as a function of time.

Each of FIGS. 2A-C shows the time dependence of the stent properties,the radial strength, drug release, mechanical integrity, and erosion ormass loss. The radial strength of the stent is maintained for a periodof time (in this case, after intervention during which the stentsupports the vessel walls. The stent then experiences a rapiddeterioration in radial strength, due to molecular weight loss, and canno longer support the lumen walls (in this case, about 3 months afterintervention). The drug release is maintained at a relatively constantlevel after intervention (in this case, between 1-1.5 months afterintervention) followed by a relatively rapid decline to zero (in thiscase, between 3-4 months after intervention). The structural integrityis maintained at a relatively constant level for a period of time afterintervention (in this case, about 3-4 months after intervention)followed by a gradual decline until a complete loss at a time greaterthan 6 months. The period of structural integrity retention is longerthan radial strength retention and the rate of decline of mechanicalintegrity is more gradual.

There are several phases of biological response and vessel changes dueto the intervention of the stent. The time period from intervention toabout 1-3 months after intervention is referred to as the acute phase.FIG. 2A depicts two biological responses to the stent that occur duringthis phase, platelet deposition and leukocyte or white cell recruitment.These biological responses can dissipate quickly if there is growth ofcellular layers over the stent.

FIG. 2B depicts additional biological responses during the acute phase,smooth muscle cell proliferation (SMP) and matrix deposition. SMP occursat the inner surface of the vessel wall in the stented section. Theexemplary profile in FIG. 2B shows that the smooth muscle cellproliferation reaches a peak between one and two months and thendecreases to negligible levels at about five months. Smooth muscle cellproliferation can be explained with reference to the structure of anarterial wall. Smooth muscle cell proliferation is expected to occurduring a time period up to about three months after implantation of thestent. Smooth muscle cell proliferation should be controlled since itcan lead to restenosis. Therefore, a bioabsorbable stent can release anantiproliferative agent, typically from a therapeutic coating layer overthe stent scaffolding to control the smooth muscle cell proliferation.The therapeutic agent release can occur up to two or four months fromintervention.

Matrix deposition involves deposition of collagen and elastin in theneointima layer, reinforcing the layer which enables it to providemechanical support. Matrix deposition is a key component of theremodeling process. Remodeling refers to a biological response thatresults in modification of the neointima layer formed from smooth musclecell proliferation that facilitates a restoration of normal function ofthe vessel.

Endothelialization refers to the formation of a layer of endothelialcells over the neointima layer and the stent. FIG. 2C, which depictscumulative endothelialization as a function of time, shows thatendothelialization starts shortly after implantation and reaches amaximum just before three months. Endothelialization results information of hemocompatible surface between the blood flow and thestent. Endothelialization plays a critical role in the healing processwith a bioabsorbable stent. Both the degree of endothelialization andtiming of the endothelialization with respect to the stent behavior arecrucial outputs. Endothelialization of the vessel wall and stent strutsis essential to prevent thrombosis associated with blood contactingstent surfaces, incomplete strut apposition (persistent orlate-acquired), and dislodgement of stent material when mechanicalintegrity of the stent fails.

The presence of a blood-contacting surface of a foreign body regardlessof the level of hemocompatibility of the bioabsorbable material of thestent, for example, presents the risk of thrombosis. In general, anendothelial layer plays a crucial role in reducing or preventingvascular thrombosis and intimal thickening. Specifically, theendothelial layer reduces or prevents deposition of proteins on thevessel wall or stent struts. Such deposition can contribute to orincrease risk of thrombosis. Therefore, early and completeendothelialization of the vessel wall and stent are essential. Completeendothelialization should occur between 4 and 6 months to reduce therisk of or avoid the thrombo-embolitic events associated with incompletestrut apposition and dislodgement of material in the vessel.

The antiproliferative drug release is necessary to avoid restenosis dueto acute phase SMP, however, it also interferes with endothelialization.Thus, antiproliferative drug release may be designed to rapidly declineto zero by 3 to 4 months after implantation so as not to interfere withendothelial growth. In a human patient, endothelial layer growth canoccur between post-stenting to 3 months, or up to six months, or morethan six months after implantation.

Therefore, stent surfaces are in contact with blood during a periodafter implantation prior to complete endothelization. The degree ofcontact is initially very high immediately after implantation anddecreases with time as endothelialization occurs. During this periodthere may be an increased risk of thrombosis arising from the contact ofthe stent with blood. The risk is expected to be greatest in the first1-2 months after implantation. It would be desirable to reduce this riskof thrombosis prior to complete endothelialization while not interferingwith either the control of SMP or endothelialization.

The stents of the present invention include modifications that improvethe hemocompatibility of stent during the period prior toendothelialization when the stent may pose a risk of thrombosis due tostent-blood contact. The modifications act synergistically withantiproliferative agents by providing hemocompatibility during andwithout interfering with antiproliferative agent release. Thehemocompatibility provided by the modification may be provided during alimited period of time, for example, during the antiproliferative drugrelease.

The risk of thrombosis presented by a stent is typically treatedsystemically with anti-coagulatents. Systemic administration can beaccomplished orally or parenterally including intravascularly, rectally,intranasally, intrabronchially, or transdermally. An anticoagulant is asubstance that prevents coagulation; that is, it stops blood fromclotting. However, systemic anti-coagulent therapy can haveside-effects. The most common side effects associated with anticoagulanttherapy are itching, rashes, easy bruising, increased bleeding frominjuries and purplish spots on the skin. Purplish skin spots are causedby small amounts of bleeding under the skin. Bruising tends to be moresevere when taking anticoagulants, and bleeding from wounds can bedifficult to stop.

The present invention provides advantages over systemic anti-coagulenttherapy. The modifications to the stent may reduce or replace systemicanti-coagulatent therapy. The modifications to the stent that providehemocompatibility are localized to the implant and can be configured toact only during the limited time that they are needed, thus do not havethe side-effects of systemic therapy.

The various embodiments of the present invention include modificationsof a bioabsorbable stent scaffold and coatings. The scaffold is composedof a plurality of interconnecting struts. Exemplary biodegradablepolymers for use with a bioabsorbable polymer scaffolding includepoly(L-lactide) (PLLA), poly(D-lactide) (PDLA), polyglycolide (PGA), andpoly(L-lactide-co-glycolide) (PLGA). With respect to PLGA, the stentscaffolding can be made from PLGA with a mole % of GA between 5-15 mol%. The PLGA can have a mole % of (LA:GA) of 85:15 (or a range of 82:18to 88:12), 95:5 (or a range of 93:7 to 97:3), or commercially availablePLGA products identified being 85:15 or 95:5 PLGA.

The fabrication methods of a bioabsorbable stent for use in the methodsof treatment described herein can include the following steps:

(1) forming a polymeric tube using extrusion,

(2) radially deforming the formed tube,

(3) forming a stent scaffolding from the deformed tube by lasermachining a stent pattern in the deformed tube with laser cutting,

(4) optionally forming a therapeutic coating over the scaffolding,

(5) crimping the stent over a delivery balloon, and

(6) sterilization with e-beam radiation.

In step (2) above, the extruded tube may be radially deformed toincrease the radial strength of the tube, and thus, the finished stent.The increase in strength reduces the thickness of the struts required tosupport a lumen with the stent when expanded at an implant site. Inexemplary embodiments, the strut thickness can be 100-200 microns, ormore narrowly, 120-180, 130-170, or 140-160 microns.

Detailed discussion of the manufacturing process of a bioabsorbablestent can be found elsewhere, e.g., U.S. Patent Publication No.20070283552, which is incorporated by reference herein. Embodiments ofthe present invention include methods of modifying the stent to providehemocompatibility of the stent, such as, during the anti-proliferativedrug release.

The therapeutic coating may include bioabsorbable coating polymer withan antiproliferative agent distributed throughout the coating polymer. Afunction of the coating polymer is to control the release of the drug.The drug release profile, for example cumulative release vs. time, maybe due to both diffusion of the drug out of the polymer and absorptionof the coating polymer. The coating polymer may be selected to have ahigher degradation rate than the scaffolding polymer to allow forrelease of the drug over the relatively shorter period of smooth cellproliferation as compared to the time for complete absorption of thescaffolding.

With respect to relative degradation rates of polymers, a first polymerhaving a “higher” or “faster degradation rate” than a second polymer mayrefer to the first polymer eroding or absorbing away completely in ashorter period of time than the second polymer. The relative degradationrates may correspond to in vitro degradation or in vivo degradation inan animal or human patient.

The two common erosion mechanisms for degradable polymers are surfaceand bulk erosion. Ideal surface eroding polymers do not allow water topenetrate into the polymer. Therefore, only a surface layer exposed tomoisture undergoes degradation and erosion. Therefore, surface erodingpolymers erode layer by layer.

In contrast, bulk eroding polymers have a high uptake of water whichdiffuses throughout the material during the degradation process.Therefore, bulk eroding polymer degrades and erodes throughout a volumeof the material. Therefore, for ideal bulk erosion the total absorptiontime is independent of the size of the piece degrading, in particular,of the thickness of a coating. However, for actual bulk eroding polymer,the degradation rate does depend on piece geometry and size.

For ideal surface erosion, the erosion rate is directly proportional toexternal surface area. Thus, for a thin flat slab, for which theexternal surface area remains constant as the slab becomes progressivelythinner, the erosion rate is essentially constant until the polymer iscompletely eroded. For a surface eroding polymer, control of the timespan the polymer persists can be achieved by adjusting the material'sdimensions and shape and by changing its chemical properties. (J. A.Tamada and R. Langer, Proc. Natl. Acad. Sci. USA Vol. 90, pp. 552-556,January 1993) Therefore, the total absorption time of a coating dependsboth on the degradation rate of the polymer at the surface and on thethickness of the coating.

An exemplary stent may include a PLLA scaffold. Exemplary bulk erodingcoating polymers for use as a carrier for drugs include PDLLA and PLGA.Both PDLLA and PLGA throughout its LA/GA composition range degrade awayfaster than the PLLA scaffolding. As shown in by in vitro data Table 1,PLLA is a relatively slow eroding polymer while PDLLA and PLGA are fastdegrading.

TABLE 1 Degradation time of bioabsorbable polymers. Polymer DegradationTime (months)^(a) PGA    6-12^(1,2) PLLA >24¹; >36² PDLLA 12-16¹; 12-15²85/15 PLGA 5-6¹ 75/25 PLGA 4-5¹ 65/35 PLGA 3-4¹ 50/50 PLGA 1-2¹ ¹MedicalPlastics and Biomaterials Magazine, March 1998. ²Medical DeviceManufacturing & Technology 2005.

Classes of polymers exhibiting surface eroding behavior that can be usedfor the surface-eroding polymer layer can include, but are not limitedto, hydrophobic aliphatic polyanhydrides, hydrophobic aromaticpolyanhydrides, polyester amides, poly(ortho esters), and polyketals.

The thickness of coating layers of the present invention may be lessthan 5 microns, or more narrowly, a thickness of 0.5-1, 1-1.5, 1.5-2,2.5-3, 3.5-4, 4.5-5, 1-2, 1-3, 2-3, 2-4, or 3-4 microns.

With regard to the discussion of coatings herein, “above” can refer toabove a surface, but not necessarily in contact with the surface, suchthat there are intervening layers between the coating layer and thesurface. “Above” can also refer to above the surface and in contact withthe surface of the scaffolding.

List Different Classes of Antithrombotic Agents

The modification of the stent to increase hemocompatibility includesantithrombotic agents disposed on the scaffolding or in or on coatinglayers. Antithrombotic agents include hydrophilic groups, sincehydrophilic surfaces in generally have been shown to be more resistantto protein adsorption and may, therefore, reduce the thrombogenicity ofa material. Hydrophilic groups can include monomers and polymers ofvarious kinds that are hydrophilic such as 2-hydroxyethylmcthacrylate(HEMA), polyethylene glycol methyl ether acrylatc (mPEG-acrylate). Any(meth)acrylated hydrophilic monomer or polymer may be used to increasehyrophilicity, including phosphorylcholine methacrylate,hydroxypropylmethacrylate (HPMA), methacrylic acid, N-vinylpyrrolidone,N,N-dimethylacrylamide, beta-carboxyethyl acrylate, N-hydroxyethylacrylamide, and hydroxypolyethoxy allyl ether.

Antithrombotic agents further include heparin and its derivatives andlow molecular weight heparin. Heparin may be immobilized by covalentbonds, such as an amide bond of an amine-containing monomer (e.g.2-aminoethylmethacrylate) that is grafted to polymer. Heparin may alsobe immobilized by covalent bonds to amino groups on a polymer. Heparinmay also be immobilized by hydrogen bonding.

Various kinds of proteins on the surface of a stent act asendothelialization promoting agents. These proteins include variousnon-adhesive proteins (e.g. albumin), cell adhesive proteins (e.g.fibronectin), or cell adhesive peptide sequences (e.g. RGD sequence).The proteins may be immobilized by a covalent bond (such as an amidebond) to an ester grafted to a polymer on the stent.

In certain embodiments of the present invention, the proteins may beimmobilized on the surface of a scaffolding, such as a PLLA scaffolding.The surface of the scaffolding may be in contact with a bioabsorbablepolymer coating that includes an antiproliferative agent. Therefore, asthe agent layer absorbs away, the immobilized proteins promoteendothelialization as the scaffolding surface becomes a blood-contactingsurface. In all of the embodiments discussed below, the scaffolding canoptionally include proteins immobilized at its surface to promoteendothelialization.

Certain embodiments of the present invention include a coating layerdisposed above all or a portion of the scaffolding composed ofbioabsorbable polymer, such as PLLA. The coating layer may include acoating polymer with bulk eroding behavior that has a faster degradationrate than the scaffolding polymer. For example, for a scaffoldingpolymer of PLLA, the coating polymer may be PDLLA and PGLA. In otherembodiments, the coating polymer is a surface eroding polymer.

In these embodiments, the coating layer may include a therapeutic agentsuch as an antiproliferative agent or an anti-inflammatory agent. Theagent may be mixed or dispersed throughout the coating layer, and thus,mixed or dispersed throughout the coating polymer. In such embodiments,the therapeutic agent may not be immobilized or chemically (i.e.,covalently) bound to the coating polymer. The agent may be free todiffuse through the coating polymer after implantation when in contactwith bodily fluids.

In some embodiments, the coating layer may contain only the coatingpolymer and the antiproliferative drug. In exemplary embodiments, thecoating polymer can be between 30-80 wt % or 40-60 wt % of the coatinglayer. In exemplary embodiments, the agent can be between 30-80 wt % or40-60 wt % of the coating layer.

When stated herein that a coating layer is free of a substance prior toimplantation, the coating layer is free of the substance except forincidental diffusion of the substance into the coating layer prior toimplantation.

In some embodiments, the first coating layer includes an immobilizedantithrombotic agent. “Immobilized” generally refers to the inability ofan agent molecule to diffuse away from a location in or on a substratematerial, such as a coating material. In the context of an immobilizedagent in or on a bioabsorbable polymer, the agent is incapable ofdiffusing away from its location in or on the coating material withoutthe chemical breakdown of the biodegradable substrate material that isdirectly or indirectly preventing the agent from diffusing. Indirect ordirect bonding of the immobilized agent to the substrate prevents theagent from diffusing. Thus, the immobilized agent can diffuse away froma substrate such as a coating polymer if the coating material thatdirectly or indirectly binds it to the coating absorbs away. Immobilizedcan also refer to substantial reduction in the ability of an agent todiffuse away from a location.

Specifically, for both bulk and surface eroding polymers, exposure ofthe coating to bodily fluids causes hydrophilic degradation of thecoating polymer which results in chain scission of the coating polymer.As degradation proceeds, the molecular weight of the species is reducedto a level that the degradation products are soluble in the bodilyfluids and are absorbed away.

The immobilization of antithrombotic agents to the coating polymermaintains the presence of the agents in or on the coating layer and thusmaintains the hemocompatibility provided by the agents during thecritical period of potential risk during drug release. Agentsimmobilized in or on the coating layer are to be contrasted with agentsimmobilized in or on durable or nonerodible coatings. Such immobilizedagents remain immobilized indefinitely since the coating does notdegrade or absorb, at least as long as the mechanism of immobilizationremains intact. Thus, in the case of a stent with a nonerodible coatingwith immobilized agents, the agents are permanent, even after they areno longer needed. In the present invention, the antithrombotic agentsmay be maintained only as long as they are needed, for example, duringantiproliferative drug release or prior to complete endothelialization.

Agents may be immobilized in various ways such as by covalent bondingthe agents to molecules of the coating polymer, either directly orindirectly. Agents may be immobilized by hydrogen bonding or ionicbonding between the agent and the coating polymer.

In some embodiments, the antithrombotic agents are immobilized only atan outer surface of the coating layer that is at a blood contactingsurface. In such embodiments, the immobilized agents can form amonolayer on the outer surface and do not penetrate into the bulk of thecoating layer. In some embodiments, the immobilized agents penetrateinto the coating layer, for example, by no more than 100 nm. Theimmobilized antithrombotic may also extend out from the outer surface ofthe coating layer agents. The immobilized agents are bound to coatingpolymer molecules only at the surface of the first coating layer. Insuch embodiments, the immobilized agents improve the hemocompatibilityof the surface. As the polymer degrades, the coating polymer at thesurface of the coating layer is absorbed or eroded away along withagents bound to the coating polymer.

When the coating polymer is a surface eroding polymer, the polymer atthe surface is eroded away first and the immobilized antithromboticagent bound to the absorbed surface polymer is also absorbed away.Therefore, the hemocompatibility provided by the antithrombotic agent islimited to the time it takes for the polymer at the surface of thecoating polymer to erode away.

This is in contrast to a coating polymer that is bulk eroding whichdegrades throughout the volume of the coating layer. The antithromboticagents at the surface thus remain intact for a longer period. An idealbulk eroding coating layer would exhibit no preferential absorption ofpolymer at the surface. However, actual behavior may exhibitpreferential absorption at the surface resulting in preferential removalof the antithrombotic agent at the surface.

FIG. 3 depicts a cross-section of a surface region of a stentillustrating the embodiments disclosed above. FIG. 3 shows a coatinglayer 150 disposed over a scaffolding 152. Coating layer 150 has athickness T. The coating layer includes a coating polymer 156 withantiproliferative agent 154 dispersed throughout the coating layer. Thecoating polymer may be a bulk eroding or surface eroding polymer. Anantithrombotic agent 158 is immobilized at the surface of the coatinglayer.

In some embodiments, the antithrombotic agent is immobilized anddistributed throughout the coating layer between an inner surface and anouter surface of the coating layer. “Inner surface” refers to surface ofa coating layer opposite to its outer layer that faces away from a bloodcontacting surface.

The presence of antithrombotic agent throughout the coating layer wouldincrease the duration of the hemocompatibility provided by theantithrombotic agent for both surface and bulk eroding coating polymersas compared to antithrombotic agent at a surface alone. The increase induration would be more significant for a surface eroding coating polymersince the surface layer with the agent erodes away first. As the surfaceeroding coating layer absorbs, antithrombotic agent that was below thesurface prior to absorption would be exposed and providehemocompatibility.

Additionally, the antithrombotic agent throughout the coating layerwould increase the duration and degree of hemocompatibility of a bulkeroding polymer as well. This would be expected to be the case even ifthere is no preferential absorption of coating polymer at the surface.Even with no preferential absorption, coating polymer at the surfaceabsorbs and antithrombotic agent immobilized to the absorbed material isremoved. The absorbed material may then expose antithrombotic agent thatis distributed below the surface which would then providehemocompatibility.

FIG. 4 depicts a cross-section of a surface region of a stentillustrating an embodiment of the present invention. FIG. 4 shows acoating layer 160 disposed over a scaffolding 162. Coating layer 160 hasa thickness T. The coating layer includes a coating polymer 166 withantiproliferative agent 164 (solid circles) dispersed throughout thecoating layer. An antithrombotic agent 158 (open circles) is immobilizedand distributed throughout the coating layer.

In further embodiments, a first coating layer may be disposed above abioabsorbable scaffolding made of a polymer such as PLLA. The firstcoating layer may be above and in contact with the PLLA scaffoldingsurface without any intervening layers. The first coating polymer mayinclude a first coating polymer that may be a bulk eroding polymer orsurface eroding polymer, as described herein. The thickness of the firstcoating layer may be any of the ranges of thickness disclosed above andother ranges such as less than 5 microns, 2-3 microns, 2.5 to 3.5microns, or 2.7 to 3 microns.

In these embodiments, the first coating layer may include a therapeuticagent such as an antiproliferative agent or an anti-inflammatory agent.The agent may be mixed or dispersed throughout the first coating layer.In such embodiments, the therapeutic agent may not be immobilized orchemically (i.e., covalently) bound to the first coating polymer. Theagent may be free to diffuse through the first coating polymer.

In some embodiments, the first coating layer may contain only the firstcoating polymer and the antiproliferative drug. The coating layer may be30-80 wt % or 40-60 wt % of drug. The coating layer may be 30-80 wt % or40-60 wt % of coating polymer. In some embodiments, the first coatinglayer is free of antithrombotic agent prior to implantation.

In such embodiments, a second coating layer may be disposed above thefirst coating layer. The second coating layer may be in contact with anouter surface of the first coating layer with no intervening coatinglayers between the first and second coating layers. The second coatinglayer may preferably include or be composed of a bulk eroding polymersuch as PDLLA or PLGA. In some embodiments, the second coating layerincludes an immobilized antithrombotic agent distributed throughout thesecond coating layer. In some embodiments, the second coating layer isfree of therapeutic agents other than the antithrombotic agent prior toimplantation. For example, the second coating layer is free ofantiproliferative or anti-inflammatory agents prior to implantation.

When the stent is implanted, the agent in the first coating layer mayelute or diffuse through the second coating layer and out of thecoating. The antithrombotic agent in the second coating layer providesincreased hemocompatibility during the delivery of the agent from thefirst coating layer. In some embodiments, the first coating polymer isthe same as the second coating polymer. For example, both the first andsecond coating polymer are PDLLA or PLGA with the same composition.

The thickness of the second coating layer can be tailored to facilitatediffusion of therapeutic agent from the first coating layer. Forexample, the second coating layer may be less than 2 microns or morenarrowly between 1-2 microns.

FIG. 5 depicts a cross-section of a surface region of a stentillustrating the embodiments discussed above. FIG. 5 shows a firstcoating layer 170 disposed over a scaffolding 172. Coating layer 170 hasa thickness T1. The first coating layer includes a coating polymer 176with antiproliferative agent 174 dispersed throughout the first coatinglayer. FIG. 5 further shows a second coating layer 180 is disposed overthe first coating layer 170. Second coating layer 180 has a thicknessT2. Second coating layer 180 includes a second coating polymer 182 andan antithrombotic agent 184 that is immobilized and distributedthroughout the second coating layer 180.

In additional embodiments, the coating layer can include immobilizedproteins on a surface of the coating layer or distributed throughout thecoating layer in addition to an antithrombotic agent such as heparin orhydrophilic monomers or polymers that are immobilized at the surface ofor distributed throughout the layer. The immobilized proteins wouldpromote endothelialization while the antithrombotic agents would providehemocompatiblity.

In additional embodiments, at least two coating layers may be disposedabove a bioabsorbable scaffolding made of a polymer such as PLLA. Insome embodiments, there are no intervening layers in between the coatinglayers. The innermost layer of the at least two coating layers (i.e.,the layer closest to the scaffolding surface) may be in contact with thescaffolding with no intervening layers between the innermost layer andthe scaffolding surface.

In some embodiments, at least one of the two coating layers includes anantithrombotic agent immobilized at a surface of or in the coatinglayer. Each of the coating layers may include an antithrombotic agent.In other embodiments, any combination of the layers may include or befree of an antithrombotic agent.

The antithrombotic agents may be immobilized only at an outer surface ofthe coating layer. In such embodiments, the immobilized agents can forma monolayer on the outer surface and do not penetrate into the bulk ofthe coating layer. In some embodiments, the immobilized agents penetrateinto the coating layer, for example, by no more than 100 nm.

In such embodiments, the immobilized agents improve thehemocompatibility of the surface of the outermost coating layer. As thepolymer degrades, the coating polymer at the surface of the coatinglayer is absorbed or eroded away along with antithrombotic agents boundto the coating polymer.

In some embodiments, each of the at least two coating layers may includeor be composed of a surface eroding polymer. Each of the coating layersmay be composed of the same surface eroding polymer. “Same” polymermeans that the polymers have the same chemical composition and molecularweight distribution. In other embodiments, the at least two coatinglayers are made of different polymers. For example, polymers can beselected based on degradation rate. The degradation rate of the coatingpolymers can increase, decrease, or alternate from the innermost layerto the outermost layer. The relative degradation rate may be adjustedbased on a desired release profile of any therapeutic agents included inthe coating layers.

In further embodiments, at least one of the at least two coating layersincludes a therapeutic agent other than an antithrombotic agentdistributed through the coating layers. The therapeutic agent may be anantiproliferative or anti-inflammatory agent. Each of the layers mayinclude the same therapeutic agent. Alternatively, any of the layers maybe free of the therapeutic agent.

In some embodiments, the thickness of each of the at least two coatinglayers may be the same. Alternatively, the thicknesses of the coatinglayers can differ. The thickness can be selected or adjusted to obtain adesired total absorption time of a coating layer. In exemplaryembodiments, the thickness of the at least two layers may be 0.5-1,0.5-1.5, for 1-2 microns. In some embodiments, the coating layers arerelatively thin such as a thickness of the coating layers is 0.1-0.5microns. Thus, the time between removal of immobilized antithromboticlayers due to surface erosion and exposure of the agents on the surfacebelow is reduced.

FIG. 6 depicts a cross-section of a surface region of a stentillustrating the embodiments discussed above. FIG. 6 shows a firstcoating layer 200 disposed over a scaffolding 202. A second coatinglayer 210 is disposed over first coating layer 200. First coating layer200 has a thickness T1 and second coating layer 210 has a thickness T2.First coating layer 200 includes a first coating polymer 204 with anantiproliferative agent 206 dispersed throughout the first coatinglayer. Second coating layer 210 includes a second coating polymer 214with an antiproliferative agent 216 dispersed throughout the secondcoating layer. First coating polymer 204 and second coating polymer 214are surface eroding polymers. An antithrombotic agent 217 is immobilizedat a surface 208 of first coating layer 200 and at a surface 218 ofsecond coating layer 210. Upon implantation of a stent of FIG. 6, theimmobilized antithrombotic agent would provide increasedhemocompatibility while the coating layer erodes and releasesantiproliferative agent.

Hydrophilic monomers or polymers may be grafted to a coating polymersurface by applying a coating material including hydrophilic monomer orpolymer to the surface of the coating polymer. The coating material canbe applied by various known methods such as spraying or dipping. Thesurface with applied coating is exposed to radiation which generatesfree radicals in the monomer and coating polymer surface. The highlyreactive free radicals result in formation of covalent linkages betweenthe coating polymer and the hydrophilic monomer or polymer.

The coating material includes hydrophilic monomer/polymer dissolved in asolvent. The solvent may be removed either after or before exposure toradiation. The coating polymer may be insoluble in the coating solvent.Alternatively, the coating solvent may be a weak solvent for the coatingpolymer, the coating solvent may swell the coating polymer, or thecoating polymer may be soluble in the coating solvent. Swelling of thecoating solvent or dissolution of the coating polymer by the solventwill result in penetration of the immobilized hydrophilic molecules intoa surface of the coating polymer. Exemplary solvents include acetone,methyl acetate, ethyl acetate, pentane, toluene, chloroform, diethylether, dichloromethane, methanol, isopropanol, and water.

A coating layer that includes immobilized antithrombotic agentdistributed throughout the layer can be made by using anitithromboticagent during preparation of the coating layer. A polymer coating on ascaffolding surface or over another coating layer may be prepared byapplying a coating material including the coating polymer and thenremoving the solvent. The coating material includes the coating polymerdissolved in a solvent. The coating material can further includehydrophilic monomers or polymers dissolved or suspended in solvent andadditional therapeutic agent such as antiproliferative andanti-inflammatory agents. The solvent is then removed throughevaporation or drying. Typically, a coating layer of a desired thicknessis achieved by repeating application and drying steps.

The finished coating layer may then be exposed to radiation whichgenerates free radicals resulting in covalent linkage between thecoating polymer and the hydrophilic monomers or polymers. The coatinglayer may also be exposed to radiation at the end of one or more of therepeated application and drying steps.

An exemplary coating material may include PDLLA dissolved in acetone orchloroform. Hydrophilic monomers or polymers are dissolved in thesolvent. An antiproliferative such as everolimus is suspended in thesolvent.

Various kinds of radiation may be used to generate free radicals, suchas electron beam (E-beam), gamma rays, and X-rays.

The methods for immobilizing hydrophilic monomers and polymers at thesurface of a coating layer and throughout the coating layer may beapplied to making the embodiments of the stents described herein, forexample, as illustrated in FIGS. 3-6.

Heparin may be immobilized in or on a surface of a coating layer inseveral ways. One technique is to immobilize heparin with amine groupsgrafted to a coating polymer. An exemplary method of immobilizingheparin on a polymer surface using this technique involves two steps.First, an amine containing (meth)acrylate monomer is grafted to thepolymer. A solution of the monomer is applied to coating layer. An aminecontaining monomer (e.g., 2-aminoethylmethacrylate) is immobilized onthe surface of the coating layer using radiation to activate freeradicals on the coating layer surface, which react with the{meth)acrylate groups to form a stable covalent bond between the monomerand the coating polymer surface. The exposure to radiation can be beforeor after the removal of solvent from the monomer solution of thesurface.

Second, the heparin is immobilized onto the amine groups formed in thefirst step. The carboxylic acid in the heparin can he activated usingN-hydroxysuccinimide and 1-Ethyl-3-[3dimethylaminopropyl]carbodiimide(NHS/EDC). Heparin and a solution of NHS/EDC are applied to a surfacewith grafted monomer. This activated group of heparin will then reactwith the amine groups on the coating polymer surface to form stableamide linkages between the heparin and the coating polymer.

A coating layer with heparin immobilized throughout the coating layermay be prepared by forming a coating layer containing a coating polymer,(meth)acrylate monomer, heparin, and NHS/EDC. The coating layer may thenbe exposed to radiation to form the monomers grafted to the coatingpolymer and the amide linkage between the monomer and the heparin.Alternatively, the first and second steps may be performed at the end ofone or more of the repeated application and drying steps used to form acoating layer.

Another technique of immobilizing heparin on a surface of a polymer usesplasma discharge. An exemplary method includes three steps.

First, oxygen plasma glow discharge is used to generate hydroxyl groupson a polymer surface.

Second, a carboxyl or amino group is then introduced on the polymersurface in order to link heparin to the surface:

1. To introduce a carboxyl group, the surface is treated with, e.g., abasic solution and then acidified to form pendant carboxyl groups(—COOH) bonded to surface polymer, for example, PDLLA-COOH.

2. To introduce an amino group, the surface is treated with, e.g.,ethylene diamine. This forms pendant amino groups (—NH2) bound tosurface polymer, for example, PLLA-NH2.

Third, heparin is immobilized to the carboxylic acid or amino group:

1. Carboxylic acid groups on the heparin are activated with, e.g.,1-ethyl 3-dimethylaminopropyl carbodiimide (EDC). A solution ofactivated heparin is then applied to the surface with pendant carboxylicgroups. Heparin is then immobilized to the activated surface using aminogroups on the heparin molecule.

2. Carboxylic acid groups on the heparin arc activated using EDC. Asolution of activated heparin is then applied to the surface withpendant amino groups. Activated carboxylic acid groups proceed toimmobilize heparin to the amino surface.

A coating layer with heparin immobilized throughout the coating layermay be prepared by performing the three steps at the end of one or moreof the repeated application and drying steps used to form a coatingpolymer layer.

The methods for immobilizing heparin at the surface of a coating layerand throughout the coating layer may be applied to making theembodiments of the stents described herein, for example, as illustratedin FIGS. 3-6.

Proteins may be immobilized on a surface of a scaffolding or coatinglayer by reaction of the proteins to an ester grafted to the surface.First, an ester in solution such as a hydroxysuccinimide estercontaining a reactive acrylate or methacrylate group is applied onto thepolymer surface. Before or after removal of the solvent from the appliedsolution, the surface is exposed to radiation, which is known to formactivated free radicals in a polymer. These activated free radicalsreact with the (meth)acrylate groups on the hydroxysuccinimide ester,forming a covalent bond between the activated ester and the coatingpolymer.

Second, proteins are then immobilized to the activated surface byreaction of the activated ester with an amine on the protein underslightly alkaline conditions to form an amide bond. This is one exampleof a method to link amine containing proteins to carboxyl groups on thebackbone, however, there are many more ways that are known. These otherways are within the scope of the present invention

A coating layer with protein immobilized throughout the coating layermay be prepared by performing the two steps at the end of one or more ofthe repeated application and drying steps used to form a coating polymerlayer.

The methods for immobilizing hydrophilic monomers and polymers at thesurface of a coating layer and throughout the coating layer may beapplied to making the embodiments of the stents described herein, forexample, as illustrated in FIGS. 3-6.

Any drugs having anti-proliferative effects can be used in the presentinvention. The anti-proliferative agent can be a natural proteinaceousagent such as a cytotoxin or a synthetic molecule. Preferably, theactive agents include antiproliferative substances such as actinomycinD, or derivatives and analogs thereof (manufactured by Sigma-Aldrich1001 West Saint Paul Avenue, Milwaukee, Wis. 53233; or COSMEGENavailable from Merck) (synonyms of actinomycin D include dactinomycin,actinomycin IV, actinomycin I₁, actinomycin X₁, and actinomycin C₁), alltaxoids such as taxols, docetaxel, and paclitaxel, paclitaxelderivatives, all olimus drugs such as macrolide antibiotics, rapamycin,everolimus, structural derivatives and functional analogues ofrapamycin, structural derivatives and functional analogues ofeverolimus, FKBP-12 mediated mTOR inhibitors, biolimus, perfenidone,prodrugs thereof, co-drugs thereof, and combinations thereof.Representative rapamycin derivatives include40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, or 40-O-tetrazole-rapamycin,40-epi-(N1-tetrazolyl)-rapamycin (ABT-578 known as zotarolimusmanufactured by Abbott Laboratories, Abbott Park, Ill.), prodrugsthereof, co-drugs thereof, and combinations thereof.

In one embodiment, the anti-proliferative agent is everolimus.Everolimus acts by first binding to FKBP12 to form a complex (Neuhhaus,P., et al., Liver Transpl. 2001 7(6):473-84 (2001) (Review)). Theeverolimus/FKBP12 complex then binds to mTOR and blocks its activity(Id.). By blocking mTOR activity, cells are unable to pass through G1 ofthe cell cycle and as a result, proliferation is inhibited. mTORinhibition has also been shown to inhibit vascular smooth musclemigration.

Any drugs having anti-inflammatory effects can be used in the presentinvention. The anti-inflammatory drug can be a steroidalanti-inflammatory agent, a nonsteroidal anti-inflammatory agent, or acombination thereof. In some embodiments, anti-inflammatory drugsinclude, but are not limited to, alclofenac, alclometasone dipropionate,algestone acetonide, alpha amylase, amcinafal, amcinafide, amfenacsodium, amiprilose hydrochloride, anakinra, anirolac, anitrazafen,apazone, balsalazide disodium, bendazac, benoxaprofen, benzydaminehydrochloride, bromelains, broperamole, budesonide, carprofen,cicloprofen, cintazone, cliprofen, clobetasol propionate, clobetasonebutyrate, clopirac, cloticasone propionate, cormethasone acetate,cortodoxone, deflazacort, desonide, desoximetasone, dexamethasonedipropionate, diclofenac potassium, diclofenac sodium, diflorasonediacetate, diflumidone sodium, diflunisal, difluprednate, diftalone,dimethyl sulfoxide, drocinonide, endrysone, enlimomab, enolicam sodium,epirizole, etodolac, etofenamate, felbinac, fenamole, fenbufen,fenclofenac, fenclorac, fendosal, fenpipalone, fentiazac, flazalone,fluazacort, flufenamic acid, flumizole, flunisolide acetate, flunixin,flunixin meglumine, fluocortin butyl, fluorometholone acetate,fluquazone, flurbiprofen, fluretofen, fluticasone propionate,furaprofen, furobufen, halcinonide, halobetasol propionate, halopredoneacetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol,ilonidap, indomethacin, indomethacin sodium, indoprofen, indoxole,intrazole, isoflupredone acetate, isoxepac, isoxicam, ketoprofen,lofemizole hydrochloride, lomoxicam, loteprednol etabonate,meclofenamate sodium, meclofenamic acid, meclorisone dibutyrate,mefenamic acid, mesalamine, meseclazone, methylprednisolone suleptanate,momiflumate, nabumetone, naproxen, naproxen sodium, naproxol, nimazone,olsalazine sodium, orgotein, orpanoxin, oxaprozin, oxyphenbutazone,paranyline hydrochloride, pentosan polysulfate sodium, phenbutazonesodium glycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicamolamine, pirprofen, prednazate, prifelone, prodolic acid, proquazone,proxazole, proxazole citrate, rimexolone, romazarit, salcolex,salnacedin, salsalate, sanguinarium chloride, seclazone, sermetacin,sudoxicam, sulindac, suprofen, talmetacin, talniflumate, talosalate,tebufelone, tenidap, tenidap sodium, tenoxicam, tesicam, tesimide,tetrydamine, tiopinac, tixocortol pivalate, tolmetin, tolmetin sodium,triclonide, triflumidate, zidometacin, zomepirac sodium, aspirin(acetylsalicylic acid), salicylic acid, corticosteroids,glucocorticoids, tacrolimus, pimecorlimus, prodrugs thereof, co-drugsthereof, and combinations thereof.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

What is claimed is:
 1. A bioabsorbable stent comprising: apoly(L-lactide) (PLLA) scaffolding composed of a plurality of strutshaving a thickness between 100 and 200 microns; and a first coatinglayer disposed over the PLLA scaffolding and a second coating layerdisposed over the first coating layer, wherein each coating layer has athickness less than 2 microns, wherein each coating layer comprises asurface eroding polymer, wherein the polymer is selected from the groupconsisting of hydrophobic aliphatic polyanhydrides, hydrophobic aromaticpolyanhydrides, polyester amides, poly(ortho esters), and polyketals,and wherein immobilized antithrombotic agent is at an outer surface ofeach coating layer, wherein the immobilized antithrombotic agent isheparin.
 2. The stent of claim 1, wherein an antiproliferative agent isdistributed throughout each layer.
 3. The stent of claim 1, wherein theantithrombotic agent is immobilized only at an outer surface of eachcoating layer or penetrates into each coating layer by no more than 100nm.
 4. The stent of claim 1, wherein the immobilized antithromboticagent is immobilized by covalent bonds to the polymer at the outersurface of each coating layer.
 5. The stent of claims 1, wherein theantithrombotic agent is immobilized only at an outer surface of eachcoating layer or penetrates into each coating layer by no more than 100nm, and wherein the immobilized antithrombotic agent is immobilized bycovalent bonds to the polymer at the outer surface of each coatinglayer.
 6. A bioabsorbable stent comprising: a poly(L-lactide) (PLLA)scaffolding composed of a plurality of struts having a thickness between100 and 200 microns; and a first coating layer disposed over the PLLAscaffolding and a second coating layer disposed over the first coatinglayer, wherein each coating layer has a thickness less than 2 microns,wherein each coating layer comprises a surface eroding polymer, whereinthe polymer is selected from the group consisting of hydrophobicaliphatic polyanhydrides, hydrophobic aromatic polyanhydrides, polyesteramides, poly(ortho esters), and polyketals, wherein immobilizedantithrombotic agent is at an outer surface of each coating layer,wherein an antiproliferative agent is distributed throughout each layer,wherein the antiproliferative agent is selected from the groupconsisting of rapamycin, structural derivatives and functional analoguesof rapamycin, paclitaxel, and taxol.
 7. The stent of claim 6, whereinthe antithrombotic agent is selected from the group consisting ofheparin, non-adhesive proteins, cell adhesive proteins, cell adhesivepeptide sequences, and hydrophilic monomers or polymers.
 8. The stent ofclaim 6, wherein the antithrombotic agent is immobilized only at anouter surface of each coating layer or penetrates into each coatinglayer by no more than 100 nm.
 9. The stent of claim 6, wherein theimmobilized antithrombotic agent is immobilized by covalent bonds to thepolymer at the outer surface of each coating layer.
 10. The stent ofclaim 6, wherein the antithrombotic agent is immobilized only at anouter surface of each coating layer or penetrates into each coatinglayer by no more than 100 nm, and wherein the immobilized antithromboticagent is immobilized by covalent bonds to the polymer at the outersurface of each coating layer.